协和医学杂志

2012, (01)

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层粘连蛋白对胰腺癌细胞内在性耐药的影响及机制研究
The Roles of Laminin in the Intrinsic Chemoresistance of Pancreatic Cancer Cell

梁智勇;任新瑜;师晓华;吴焕文

摘要(Abstract):

目的 探讨胰腺癌细胞系中层粘连蛋白(laminin,LN)对胰腺癌细胞内在性耐药的影响,并进行初步的机制探讨。方法 选择胰腺癌细胞系AsPC-1,检测LN对Gem细胞毒性以及LN对Gem诱导细胞凋亡能力的影响。通过Western blot等方法检测LN对下游FAK、Akt、ERK1/2、Bad 、survivin等蛋白表达及磷酸化改变。进而,在AsPC-1中,过表达FAK内源竞争性抑制剂FRNK,或应用FAK 特异性小分子抑制剂PF-573,228抑制FAK磷酸化与活性,检测FAK及其下游信号的抑制对LN作用的影响。结果 在胰腺癌细胞系AsPC-1中,LN处理使得Gem的细胞毒性以及Gem诱导细胞凋亡能力显著降低。LN能够时间依赖性上调AsPC-1 细胞内FAKTyr397位点及Akt的磷酸化水平,LN还可以显著增加AsPC-1细胞的survivin蛋白表达水平及BADSer-136位点磷酸化水平。过表达FRNK或应用PF-573,228能够显著抑制FAK磷酸化水平以及其下游通路的活化,并能够对抗LN对胰腺癌内在性耐药的效应。结论 细胞外基质蛋白 LN能够诱导胰腺癌细胞系对Gem的内在性产生耐药。LN影响胰腺癌细胞内在性耐药的具体机制可能与 FAK磷酸化以及其下游PI3K-Akt通路活化、Bad Ser-136位点磷酸化与survivin表达水平改变有关,FAK靶向治疗与Gem联合在胰腺癌治疗中具有重要的潜在应用价值。
Objective To determine the effects of LN on the intrinsic chemoresistance of pancreatic cancer and whether these effects are mediated by LN-induced FAK phosphorylation and subsequent downstream signal pathway. Methods The effects of LN on Gem-induced cytotoxicity and apoptosis in pancreatic cancercell line AsPC-1 cells were determined by MTT, Clonogenic assay and apoptosis analysis。And the effects of LNon the expression and phosphorylation of FAK,Akt and ERK1/2 were detected by western blot。Then,we explored the changes in the effects of LN in AsPC-1 cells by FAK phosphorylation inhibition through FRNK overexpression or specific FAK phosphorylation inhibitor PF-573,228. Results We found that in AsPC-1 cells LN decreased Gem-induced cytotoxicity and apoptosis,induced FAK and Akt phosphorylation in a time dependent manner and increased the levels of survivin and pBad (pS136). Specific inhibition of LN-induced FAK phosphorylation by either FRNK overexpression or PF-573,228 suppressed the effects of LN on AsPC-1 cells. Conclusions our research demonstrates that LN contribute to increased intrinsic chemoresistance to Gemin pancreatic cancer cell and these effects are due to the regulation of FAK, Akt and Bad phosphorylation and survivin expression. The Application of Selective FAK inhibitors may be a promising way to enhance chemosensitivity in pancreatic cancer.

关键词(KeyWords): |层粘连蛋白|胰腺癌|化疗耐药|粘着斑激酶|
|laminin|pancreatic cancer| gemcitabine chemoresistance| FAK|

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作者(Author): 梁智勇;任新瑜;师晓华;吴焕文

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